Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide

Nature. 2007 Oct 4;449(7162):564-9. doi: 10.1038/nature06116. Epub 2007 Sep 16.

Abstract

Plasmacytoid dendritic cells (pDCs) sense viral and microbial DNA through endosomal Toll-like receptors to produce type 1 interferons. pDCs do not normally respond to self-DNA, but this restriction seems to break down in human autoimmune disease by an as yet poorly understood mechanism. Here we identify the antimicrobial peptide LL37 (also known as CAMP) as the key factor that mediates pDC activation in psoriasis, a common autoimmune disease of the skin. LL37 converts inert self-DNA into a potent trigger of interferon production by binding the DNA to form aggregated and condensed structures that are delivered to and retained within early endocytic compartments in pDCs to trigger Toll-like receptor 9. Thus, our data uncover a fundamental role of an endogenous antimicrobial peptide in breaking innate tolerance to self-DNA and suggest that this pathway may drive autoimmunity in psoriasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimicrobial Cationic Peptides / metabolism*
  • Autoantigens / immunology
  • Autoantigens / metabolism*
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / metabolism*
  • Autoimmune Diseases / pathology
  • Autoimmunity*
  • Cathelicidins
  • DNA / immunology
  • DNA / metabolism*
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism*
  • Endocytosis
  • Endosomes / immunology
  • Endosomes / metabolism
  • Humans
  • Psoriasis / immunology
  • Psoriasis / metabolism*
  • Psoriasis / pathology
  • Toll-Like Receptor 9 / immunology
  • Toll-Like Receptor 9 / metabolism

Substances

  • Antimicrobial Cationic Peptides
  • Autoantigens
  • Cathelicidins
  • TLR9 protein, human
  • Toll-Like Receptor 9
  • CAP18 lipopolysaccharide-binding protein
  • DNA